Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents

Abstract

Previous preclinical work has demonstrated the therapeutic potential of antagonists of the group II metabotropic glutamate receptors (mGlus). Still, compounds that are selective for the individual group II mGlus (mGlu2 and mGlu3) have been scarce. There remains a need for such compounds with the balance of properties suitable for convenient use in a wide array of rodent behavioral studies. We describe here the discovery of a selective mGlu3 NAM 106 (VU0650786) suitable for in vivo work. Compound 106 is a member of a series of 5-aryl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one compounds originally identified as a mGlu5 positive allosteric modulator (PAM) chemotype. Its suitability for use in rodent behavioral models has been established by extensive in vivo PK studies, and the behavioral experiments presented here with compound 106 represent the first examples in which an mGlu3 NAM has demonstrated efficacy in models where prior efficacy had previously been noted with nonselective group II antagonists.

Exposure to the predator odor TMT induces early and late differential gene expression related to stress and excitatory synaptic function throughout the brain in male rats

“…Group II mGluRs play an important role in stress, with several studies demonstrating a functional role of these receptors in stress-induced anhedonia/depressive-and anxiety-like behavioral phenotypes 44,45,46,47,48 . Negative allosteric modulation of mGluR3 has antidepressant-like effects in the forced swim and marble burying tests 49 . Interestingly, mGluR3mediated long-term depression (LTD) on excitatory prelimbic neurons was abolished following restraint stress 45 , which is consistent with our findings that TMT stress downregulates GRM3 expression in the prelimbic cortex.…”

Co-Activation of Metabotropic Glutamate Receptor 3 and Beta-Adrenergic Receptors Modulates Cyclic-AMP and Long-Term Potentiation, and Disrupts Memory Reconsolidation

“…LY379268, propranolol, CCPA, and PQ69 were purchased from Tocris (Ellisville, Missouri). MNI-137 (Hemstapat et al, 2007), BINA (Galici et al, 2006), VU0469942 (Wenthur et al, 2013), and VU0650786 (Engers et al, 2015) were synthesized as previously described. Unless otherwise stated, all other reagents were purchased from Sigma-Aldrich (St Louis, Missouri).…”

“…Propranolol, LY379268, CCPA, and PQ69 doses were based ranges in previously published studies showing efficacy in vivo (Concas et al, 1993;Lu et al, 2014;Pitsikas and Markou, 2014;Taherian et al, 2014). VU0650786 dosing was selected based on our extensive previous in vivo studies (Engers et al, 2015). All compounds for behavioral experiments were formulated with 10% Tween 80 in sterile water and the pH was adjusted to 7.4 with NaOH and injected at a volume of 2 ml/kg.…”

Targeting metabotropic glutamate receptors in the treatment of epilepsy: rationale and current status

“…However, the pharmacodynamic synergism between mGlu 2 receptor PAMs and levetiracetam [71,72] holds promise from a therapeutic standpoint. The recent availability of mGlu 2 -and mGlu 3 -selective NAMs will help to elucidate the precise role of the two receptor subtypes in the pathophysiology of epilepsy [96][97][98][99].…”